Summary of Work: The tracheobronchial epithelium produces mucins, which protect the epithelium against toxic chemicals and microbial agents. However, hypersecretion of mucin is a common and often severe complication of many inflammatory diseases of the airways. The purpose of our studies is to determine factors and mechanisms regulating mucin genes and mucin secretion. We previously reported that MUC5AC mucin gene expression in human airway epithelial cells is controlled by retinoic acid (RA) via the retinoic acid receptor (RAR)-alpha and that triiodothyronine (T3) inhibits MUC5AC expression. Further analysis showed that T3 strongly inhibited MUC5AC-driven luciferase activity in NHTBE cells transiently transfected with a MUC5AC luciferase reporter construct, however it did not effect MUC5AC mRNA stability. This indicates that T3 suppresses MUC5AC expression at the transcriptional level. Western analysis showed that T3 markedly decreased several types of retinoid receptors while not affecting T3 receptor proteins. Consistent with this finding, gel shift assays revealed a reduction of RAR:RXR-RARE complexes obtained from T3 treated cells. The results suggest that T3 inhibits retinoid-dependent MUC5AC expression by reducing retinoid receptor levels and thereby reducing transcriptional activation of this mucin gene. Other studies aimed at the regulation of mucin gene expression and the secretion of mucin by inflammatory mediators showed that RAR-alpha antagonist inhibited the expression of MUC2 and MUC5AC mRNAs increased by tumor necrosis factor-alpha, interleukin-1beta, lipopolysaccharides, and neutrophil elastase.